SARCOPENIA VS CACHEXIA: MUSCLE LOSS CAUSES, PREVENTION AND TREATMENT

Muscle is increasingly gaining attention for its role in metabolism and health promotion. As a common effect of aging and various states of disease, muscle wasting is known to substantially affect one’s quality of life and increase the risk for all-cause mortality.

The following discussion takes a brief look at two of the most prominent muscle wasting conditions, sarcopenia and cachexia, covering differences, similarities, treatment options and prevention tips.

A Brief Look at Muscle Development

Muscle tissue is known to develop in response to use, which is required in order to move or maintain posture. At the cellular level, exercising a muscle promotes both pro and anti-inflammatory factors from cells lining the blood vessel walls within muscle tissue. These promote muscle stem cells to mobilize and contribute towards muscle building. During injury, illness or disease states, immune markers emitted from muscles and blood vessels attract immune cells such as macrophages in order to aid the repair process. These immune cells tend to remove cell debris, toxins and foreign particles that may hinder repair. They also release growth factors that promote stem cell activation and anti-inflammatory compounds that can serve to balance or put an end to toxin removal (an inflammatory process). In muscle wasting diseases, disruptions at any stage of these processes can contribute to degeneration and faulty muscle function.^[1]

Muscle Fiber Types. Muscles can be divided into smooth muscle and striated muscle, as well as slow or fast muscle. Slow muscle consists of type I fibers, while fast muscle consists of type II fibers that are further divided into IIA, IIB and IIX type fibers^[2]. Muscle fibers are often present in different ratios across organs and muscle groups and are able to fulfill different functions depending on their distinct metabolic profiles. In muscle wasting conditions, wasting may only occur in select fiber types or in a combination. The most prominent types are further discussed below:

• Fast muscle fibers have more contractile force and work through anaerobic metabolism, meaning that they can generate and make use of ATP in the absence of oxygen. They can be found in the largest quantities in the peripheral muscles^[3]. These types act faster than their slow counterparts, reflected in their higher propensity for handling calcium gradients which stimulate muscle contraction. Due to their quicker action, fast muscle fibers tire out more quickly than slow muscle fibers.^[4] Compared to slow fibers, they are more sensitive to muscle disuse than to malnourishment or starvation.
• Slow muscle fibers work off of aerobic metabolism, which means they require oxygen in order to make use of and generate ATP. They are located more in postural muscles along the neck and spine^[5]. These fibers are slower and typically generate less energy during exercise. Slow muscles are more sensitive to starvation than to disuse.

Factors Known to Affect Muscle Growth

Throughout the lifespan, muscle tissue is maintained via several tight-knit cellular pathways that regulate both muscle building and breakdown.

Factors that increase general growth in the body can promote muscle building. These include:

Sex Hormones. Both testosterone and estrogen play roles in promoting muscle growth in men and women, respectively^{[6] [7]}. Hormones can be affected by metabolic deficits, circadian disruption, states of disease and aging. Healthy bone signaling and the cross-talk between bone and muscle have also been implicated in muscle building^[8]. Sex hormone supplementation in aged men and women has been noted to improve bone mineral density and signaling^{[9] [10]}, alongside weight-bearing exercise and adequate protein and mineral intake.

Growth Factors, including insulin-like growth factor 1 (IGF-1), are known to stimulate muscle growth. Many of the factors known to promote muscle growth generally increase growth factor levels in the body, including protein consumption and exercise.

Hunger Hormones and Increased Food Intake. Ghrelin, the hunger hormone, is implicated in promoting muscle growth via increasing food intake and the direct release of growth factors. Appetite suppression, whether induced by aging, starvation, disease, brain changes or inflammation, can all lower both ghrelin and growth factors. While a diminished appetite and lower food intake can contribute towards muscle wasting conditions, cachexia and sarcopenia are distinct from starvation, as consuming more food does not tackle the underlying cause or resolve them.

Branched-Chain Amino Acids. Increased intake of dietary protein can enhance muscle growth, particularly when coupled with exercise and muscle use. Despite the benefits of increased protein intake, the majority of dietary proteins do not contribute towards muscle protein synthesis. Branched-chain amino acids (BCAA) are known to play a central role in muscle building. After a meal enriched with BCAA, muscle tissue responds postprandially by inhibiting muscle breakdown and stimulating muscle protein synthesis resulting in improved muscle formation. Out of these, leucine appears to have the greatest muscle-building effect, which is mediated via its main metabolite, beta-hydroxy beta-methylbutyrate (HMB). Only 5% of ingested leucine is converted into HMB.

Muscle Contraction and Use. Myosin and actin are the main proteins found in muscle fibers that are responsible for their contraction and relaxation. During contraction, ATP is broken down into ADP and phosphorus, which releases stored energy and serves to push myosin and actin complexes together. When together, the muscle is contracted and the compression of the two protein complexes creates the strength required to exert a counter force required to use the muscle.^[11] Muscle use promotes muscle protein synthesis^[12], whereas disuse has been associated with muscle atrophy due to protein loss. This process is accompanied by factors that further serve to regulate muscle building and regulate other aspects of metabolism, including immune function, bone growth and fatty tissue regulation.

Risk Factors That Enhance Muscle Atrophy

The below factors are associated with muscle breakdown and atrophy:

Muscle Disuse. When not in use, muscle fibers shrink in size^[13], contractile protein content decreases (due to a lowered need for synthesis^[14]), and as a result, the muscles lose power. A lack of muscle use has also been noted not only to enhance wasting but to promote resistance towards muscle building. The complex mechanisms underlying muscle protein synthesis, growth and atrophy are still being investigated. It is currently understood that short-term muscle disuse leads to changes in muscle tissue that detract from protein synthesis and increase protein breakdown. Coupled with these changes are lowered insulin sensitivity (suggestive of reduced metabolic activity and energy production) and potential degradation of the nerves found in muscle tissues.^[15] Interestingly, ATP appears to be required for relaxing muscle tissue and is generated during physical activity. Lowered ATP levels may increase muscle contraction and stiffness, potentially contributing towards muscle changes preceding atrophy.

Glucocorticoid Excess may also be a contributing factor to general muscle loss^[16] and elevated glucocorticoids are often seen in patients with muscle wasting diseases^[17]. Several treatments that increase glucocorticoids or activate their receptors are associated with promoting muscle wasting, including steroids and chemotherapy.^[18]

Inflammation can detract from muscle growth in a number of different ways, including by being the result of mitochondrial dysfunction, injury, or diminishing nerve function. It can also give rise to faulty blood vessel signaling^[19], toxins, chronic infectious illness or unbalanced immune cell signaling. [1] [2] Inflammation can elevate and increase by factors such as myostatin and activin that inhibit protein accumulation and muscle development^[20]. All conditions of muscle wasting tend to predispose the individual towards a higher risk for weakness and contracting muscle injuries, which can also promote an increase in inflammation and atrophy.

Nutritional Deficits may contribute to muscle wasting diseases and sarcopenia by exacerbating underlying metabolic problems. Some main nutrients that are commonly affected in individuals with muscle wasting conditions are discussed below:

• Zinc Imbalance. Zinc is known to regulate many cellular processes in the body, including muscle protein synthesis. During conditions of zinc deprivation, the body mobilizes zinc preferentially to muscle, lung and pancreatic tissues. It is noted that zinc deficiency promotes the deterioration of slow muscle fibers^[21], which may contribute to more severe forms of sarcopenia and cachexia. Animal studies suggest that zinc deficiency can disrupt muscle mitochondrial function (including their growth and repair) and increase apoptosis in muscle tissues^[22], suggesting that zinc is required to generate the energy needed to build muscle as well. Exercise promotes a transient increase in blood zinc levels as well as an upregulation in zinc transporters, which likely contributes towards the redistribution and incorporation of both zinc and proteins into muscle and other tissues where it is required. Zinc is commonly found in protein-heavy whole foods and therefore, supplementation is only warranted in cachexic (or sarcopenic) patients with severe zinc deficiency or immune dysfunction. Zinc serves to regulate various aspects of immune dysfunction and inflammation and hence may be a better supplement for those with disease-related cachexia, as opposed to sarcopenia.
• Vitamin D Deficiency. Vitamin D3 has been shown to be involved in regulating muscle tissue and function, specifically through enhancing muscle contraction and strength. Low levels of vitamin D3 have been associated with promoting muscle atrophy^[23], particularly in aged individuals and in those with comorbid diseases indicative of deficiency. Supplementation is noted to improve muscle strength in those with low muscle mass.^[24]

Sarcopenia vs. Cachexia: Differences and Similarities

While both conditions are indicative of muscle wasting, cachexia and sarcopenia are usually the result of unique underlying causes. The differences and similarities are reviewed below.

Sarcopenia

Sarcopenia refers to age-related muscle and strength loss. It is associated with frailty and the risk of poor health outcomes during aging, such as falls, fractures, less mobility, disability, reduced life quality, morbidity, increased time spent hospitalized and mortality. While frailty is a symptom of sarcopenia, it was shown to be more common amongst the elderly than sarcopenia itself. The aging process lends itself to sarcopenia through lowered hormone production, reduced food intake^[25], and the build-up of faulty aged cells.

Neuromuscular Junction Atrophy. Sarcopenia is thought by some researchers to be a neuromuscular junction disease, as age-related denervation has been shown to play a prime role in sarcopenia-induced muscle wasting. As seen in cachexia, muscle weakness and increased calcium sensitivity is seen in those with sarcopenia. However, the mechanisms that produce these effects differ^[26]. Aged cells display a unique inflammatory profile that possibly contributes to neuromuscular aging.^[27] Exercise has been shown to reverse these age-related effects^[28] and enhance muscle strength.

Type I Dominance. Long-term muscle disuse is associated with promoting age-related sarcopenia due to muscle changes that are known to accumulate throughout the lifespan as a result of injury and illness.^[29] It is dominated by the atrophy of fast muscle fibers, resulting in a higher dependence on slow muscle fibers.^[30] In this respect, those with sarcopenia require a higher degree of oxygenation to the muscles in order to promote optimal energy production and use.

Senescent Muscle Stem Cells. Muscle stem cells appear to be diminished and faulty in aged individuals with sarcopenia. This is ascribed to the age-related changes in senescent cells, including their unique inflammatory markers, cell membrane alterations and hyper-secretory activity.^[31]

Age-Related Immune Alterations. The number of immune cells is lower in aged individuals and displays a senescent profile. In sarcopenia, a higher proportion of anti-inflammatory macrophages (M2) are present as compared to their inflammatory counterparts (M1). In conjunction with aged muscle and stem cells, these M2 macrophages promote an increase of fat growth in muscle tissue while opposing the removal of senescent cells.^[32]

Cachexia

Cachexia refers to disease-related muscle atrophy, which is perpetuated by chronic inflammation and is often accompanied by fat wasting. Clinically it has been defined as a drastic muscle mass loss of 5% or more over the last 6 months. Unlike sarcopenia, cachexia often presents with a higher degree of systemic inflammation and an elevated metabolic rate, in line with increased muscle and fat breakdown. It is thought to be the result of a dysfunctional metabolism^[33].

Cachexia-Related Disease. Many diseases can promote the occurrence of cachexia, including hereditary muscle disorders, COPD, kidney disease, cancer, anorexia, chronic infections, AIDS and chronic heart failure^[34]. Cancer is the most commonly used model for the study of cachexia. However, differences have been noted between cachexia forms from other disease states. Not all diseases that involve muscle wasting present with cachexia, such as seen in depression and eating disorders, in which starvation is usually the primary cause of muscle wasting.

Muscle Fiber Wasting. Acute periods of muscle disuse in relation to states of disease are highlighted as a larger contributor to cachexia than to sarcopenia. Cachexia was previously believed to be characteristic of a type 2 muscle fiber dominance. However, recent experimental studies have indicated that cancer cachexia can present with even muscle atrophy of both type 1 or 2 fibers.

Mitochondrial Dysfunction in Cancer Cachexia. The mitochondria are shown to be greatly impaired in mice models of cancer cachexia, resulting in lower energy output and impaired muscle building. Despite lower muscle mass, blood vessels to the muscles appear to remain intact and are still able to supply the area with adequate oxygen and nutrient substrates, suggesting that inflammation control and mitochondrial repatriation are essential for this group of patients. Other studies suggest that this energy impairment may also contribute towards an elevated metabolic rate, an increase in protein breakdown for use as a fuel substrate, faulty mineral handling and a lesser ability for protein storage in skeletal muscle, all of which would perpetuate cachexia-induced muscle wasting.^[35]

Inflammatory Markers. Non-muscle derived interleukin-6 (IL-6) and several other inflammatory markers have all been shown to contribute towards muscle wasting across all types of cachexia. Muscles release anti-inflammatory IL-6 (different from conventional IL-6) during exercise, which may partially explain the improvements seen with exercise in patients with muscle wasting. Specific to cancer cachexia, tumors are known to block muscle-protective signals in order to fuel their growth^[36]. This is seen with metabolic disturbances that lend themselves to rerouting muscle proteins to the liver for glucose conversion in order to sustain tumor growth. Other proteins, including albumin, transferrin, C-reactive protein, fibrinogen and other protein-rich cellular products, have also been noted to serve as a fuel for tumor growth in this regard.

Lower Muscle Strength. Strength is reduced overall in cachectic muscle as compared to the same amount of muscle tissue in healthy controls. Further investigation revealed that cachectic cancer patients display higher or lower sensitivity towards calcium and increased glutamate handling in the energy production cycle, both of which could contribute to lowering contractile force in muscle tissues. In contrast to sarcopenia, the neuromuscular junction in cancer patients with cachexia is often unaffected.

Commonalities Between Cachexia and Sarcopenia

Sarcopenia, cachexia and malnourishment may be present in the same patient.^[37] All of these conditions share a major overlap in symptoms, such as muscle wasting, fatigue, exhaustion, lowered strength and reduced mobility. Joint factors that can provoke sarcopenia and cachexia include reduced appetite or food intake, inflammation, hormonal decline or fluctuation, lower physical activity, diminished mitochondrial function^[38] and increased nutritional and energy requirements.^[39]

Protein Imbalance. In the same way that body fat serves as a reservoir for lipids that can be used as an energy source, so too does muscle tissue function as a protein reservoir. Proteins are vital for generating energy, regulating metabolism, building cellular products and promoting cell growth and division in general. Lowered protein digestion and absorption can contribute towards both sarcopenia and cachexia, as the body starts to metabolize muscle fibers in order to compensate for its protein needs. This is one main reason that physical activity is known to help most conditions indicative of muscle wasting, as it causes the body to adapt to an increased metabolic need for proteins in muscle tissue.^[40] In addition to muscle tissue protein depletion, the body may turn towards using alternative protein sources to fuel energy production, such as blood albumin. More energy is required for the process of converting protein to ATP as it generates excess nitrogen, for which ATP is needed for urea conversion and disposal. This further contributes to underlying energy deficits that can perpetuate muscle wasting diseases.

Fat Metabolism. Despite fat wasting being common to muscle wasting conditions, obesity can be observed in some patients with cachexia or sarcopenia^[41]. Additionally, it appears to be common for fat and calcium deposits to accumulate in cachectic muscle tissue. If fat metabolism is healthy in the individual, increased fat burning may help to initially compensate for muscle breakdown, as evidenced by the beneficial effects of ketone bodies in muscle tissues^{[42] [43]}. Unbalanced fat metabolism may explain why fat might accumulate in deposits in skeletal muscle. As overall liver function is implicated in perpetuating muscle wasting changes^[44], maintaining optimal liver health and stable fat metabolism are indicated for those with muscle wasting conditions.

Angiotensin II. Inflammatory markers and glucocorticoids are known to be increased in response to elevated angiotensin II, alongside reductions in growth factor levels and hunger-stimulating hormones. Angiotensin II has been shown to provoke general muscle wasting by stimulating the ubiquitin-proteasome system, as well as inhibiting other major regulators of muscle growth in the body^[45]. Excess glucocorticoids may increase angiotensin II expression or modulate receptor function in a way that exacerbates muscle breakdown. These effects have been partially combated through the use of angiotensin receptor blockers^[46] and ACE II inhibitors. Both growth hormone resistance and insulin resistance have been implicated in promoting muscle wasting in chronic heart failure patients, which is associated with an increase in angiotensin II. ^[47] Nevertheless, the development of insulin and growth hormone resistance in these conditions is typically multifactorial. More research is required to confirm whether ACE II inhibitors would be an appropriate option for this patient group.

Current Treatment Options

There are currently no recognized treatment options for cachexia or sarcopenia. Prevention, early detection and management are known to be the best current therapies available. For those with either sarcopenia or cachexia coupled with a comorbid disease, it is very important to tailor a treatment program with a skilled healthcare professional, especially if enduring mid to late-stage disease.

In Sarcopenia (in the absence of other disorders), resistance training, increasing food intake and maintaining a high protein intake (20-35g) with every meal are advisable.^[48] While potentially useful, these measures may promote problems in those with cachexia, depending on the associated disease state, progression and severity. A larger amount of BCAAs, especially leucine (10-15g per meal or 3g leucine per meal), may help to overcome muscle protein degradation. Interestingly, a main leucine metabolite is a specific form of butyrate (a gut-derived short-chain fat), which is known to enhance protein accumulation and muscle building. Hormone replacement may assist menopausal and postmenopausal women in building muscle.^[49] Senolytics and senotherapeutics may be another option for those with sarcopenia. These are compounds capable of suppressing specific inflammatory factors associated with aged cells.

Potential for Electrical Stimulation in Sarcopenic Patients. Preliminary studies suggest that electrical muscle stimulation may help to improve muscle fiber growth and strength. Elderly individuals with sarcopenia, reduced muscle coordination and strength were given electrical stimulation therapy for 2-3 times a week prior to exercise sessions over a 9 week period. The results showed greatly improved muscle growth, muscle fiber number and strength in the participants compared to the controls. Growth factors were also noted to be improved in the participants as a result of the stimulation.^[50]

In Cachexia, disease-specific interventions are required to improve appetite, lower inflammation, correct nutritional deficits and help to improve overall metabolism. In some cases, gentle exercise (resistance and aerobic) and branched-chain amino acids may serve to improve muscle mass and appetite. These may be contraindicated depending on the disease state and severity^[51], such as in kidney disease, where protein handling proves problematic^[52].

Potential Pharmaceutical Treatments for Cachexia. Pharmaceuticals are more often prescribed to treat the underlying cause of disease rather than muscle wasting. The following may be prescribed to patients with cachexia:

• Corticosteroids are sometimes prescribed for short periods of time to suppress inflammation and improve appetite. However, excess corticoids may promote muscle wasting and are not advised in the long run.
• Beta-2 Blockers may help to improve heart muscle wasting in those with heart disease, yet results are contradictory in the context of other muscle wasting conditions.
• Other therapies that have shown preliminary promise include NSAIDs and omega-3 fats, both of which serve to lower inflammation. While both of these compounds have been found to be used frequently among those with cachexia, there is not enough data to make a solid conclusion.^{[53] [54]} NSAIDs have been shown to help prevent cachexia when frequently used prior to diagnosis.

Prevention Tips

As the risk for both disease-related cachexia and sarcopenia increases with age, prevention is pertinent for everyone. Research suggests that the following may be beneficial for conserving muscle throughout life:

• Physical Activity is one of the most useful interventions one can make use of in order to promote muscle building. Muscle tissue responds to physical activity and muscle contraction by increasing protein synthesis and lowering muscle protein degradation. Moreover, physical activity and its positive effects on muscle metabolic regulation have also been implicated in regulating immune function throughout the lifespan and during aging.^[55] While most forms of exercise are beneficial, resistance exercise has consistently proven to be the most effective. Athlete studies suggest that endurance exercise promotes the development of type I fibers and may be beneficial for cachexic patients, while strength-promoting exercise is associated with type II fiber development and may be more beneficial for those with sarcopenia.^{[56] [57]} Despite these findings, experts recommend a variety of exercise types for balanced muscle building and overall health.^[58]
• Pre-Exercise Stretches and Warm-Ups. In sarcopenia, exercise has been shown to bolster the number of type I muscle fibers and helps to combat age-related muscle atrophy. Due to the nature of type I fibers, it may be more pertinent for aged individuals to stretch and loosen the joints prior to exercise in order to enhance blood flow. Animal studies revealed that pre-exercise stretches might similarly help to improve upon symptoms of cachexia through stimulating blood flow, leading to mildly enhanced protein retention and muscle building^[59].
• Improving Gut Health. The gut microbiome and digestive health have both been shown to affect one’s overall state of health. In recent years, a connection between the gut and muscle tissue has been established, revealing that gut-derived metabolites are capable of regulating inflammation and promoting optimal muscle function and turnover. Improving microbial diversity can help one to digest protein, absorb other beneficial nutrients, and increase microbial short-chain fat production (such as muscle-enhancing butyrate). Consuming prebiotic foods and probiotic condiments in the context of a balanced, nutrient-dense diet serves to promote microbial diversity and enhance overall digestive health. This is also linked with supporting liver function and fat metabolism, which, when coupled with optimal protein consumption, may serve to enhance muscle building.
• Dietary Antioxidants. Certain antioxidant nutrients have proven to conserve muscle tissue when it is not in use^[60], as well as to lower the risk of injury, lower inflammation and enhance gut microbiome health. Phytochemicals in foods^[61], such as tannins, flavonoids, digestive enzymes and various amino acids like cysteine are all examples. Vitamin E and C are also known to be muscle-protective, particularly in the context of injury and repair. Nutrient-dense diets have generally been associated with better aging outcomes and a lower risk of contracting disease, which may further protect against muscle wasting conditions.

Conclusion

Conserving muscle mass is known to promote overall health through optimizing metabolic signaling, immune function and everyday activities. Disease and aging are associated with cachexia and sarcopenia, which are the most prominent forms of muscle wasting in the population. Metabolic disturbances were shown to be common features of both conditions, which can be exacerbated by reduced food intake, muscle disuse, and excessive corticoid levels. Depending on the individual’s state of health, exercise and increasing both protein and nutrient intake are recommended for both treatment and prevention. These measures are seen to be more effective in the context of sarcopenia, whereas patients with cachexia are likely to require more personalized programs aimed at improving muscle mass.

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